2-Aryl benzazole derived new class of anti-tubercular compounds: Endowed to eradicate mycobacterium tuberculosis in replicating and non-replicating forms

• Published in: Bioorganic chemistry 2020-10, Vol.103, p.104170-104170, Article 104170
• Main Authors: Velappan, Anand Babu, Datta, Dhrubajyoti, Ma, Rui, Rana, Shiwani, Ghosh, Kalyan Sundar, Hari, Natarajan, Franzblau, Scott G., Debnath, Joy
• Format: Article
• Language: English
• Subjects: Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; Benzazole; FtsZ enzyme; Humans; MenG enzyme; Mycobacterium tuberculosis - drug effects; Tuberculosis
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104170

[Display omitted] •Dual targeted 2-Aryl benzazole derivatives.•Compound 9m and 9n found equally active against replicating and non-replicating Mtb.•Inhibit the cell division by inhibiting GTPase activity of Mtb-FtsZ.•Capable to kill Mtb in non-replicating form by inhibiting menaquinone biosynthesis. The high mortality rate and the increasing prevalence of Mtb resistance are the major concerns for the Tuberculosis (TB) treatment in this century. To counteract the prevalence of Mtb resistance, we have synthesized 2-aryl benzazole based dual targeted molecules. Compound 9m and 9n were found to be equally active against replicating and non-replicating form of Mtb (MIC(MABA) 1.98 and 1.66 μg/ml; MIC(LORA) 2.06 and 1.59 μg/ml respectively). They arrested the cell division (replicating Mtb) by inhibiting the GTPase activity of FtsZ with IC50 values 45 and 64 μM respectively. They were also capable of kill Mtb in non-replicating form by inhibiting the biosynthesis of menaquinone which was substantiated by the MenG inhibition (IC50 = 11.62 and 7.49 μM respectively) followed by the Vit-K2 rescue study and ATP production assay.